Dental caries is an infectious disease caused by oral acid-producing bacteria such as Streptococcus mutans and Streptococcus sobrinus, characterized by dental parenchyma loss due to an imbalance between decalcification and recalcification. In a currently available therapeutic method for teeth with dental caries that reached the dentin as well as pulp, a calcium hydroxide preparation is applied as a pulp-capping agent to the exposed pulp, and thereafter dental cement and the like are filled. However, in this method, a necrotic layer occurs on the pulp face in contact with calcium hydroxide, and the damaged pulp tissue never regenerates, with only slight formation of tertiary dentin under the necrotic layer.
Both dentin and pulp are tissues derived from mesenchymal stem cells, but they were in the past considered different tissues, the former as hard tissue, and the latter as soft tissue. Recent studies have recognized them as an embryologically and functionally integrated tissue, called “a dentin-pulp complex”. Odontoblasts in pulp are known to extend their processes into dentinal tubules, and to play a role as a sensor for exogenous stimuli; the physiological morphology and function of the dentin-pulp complex are deeply involved in the survival of a tooth. For this reason, the prognosis with the above-described currently available therapy is not good at all.
Basic fibroblast growth factor (hereinafter sometimes abbreviated bFGF) is a peptidic cell growth factor confirmed to be present in the pituitary, brain, retina, corpus luteum, adrenal, kidney, placenta, prostate, thymus, chondrosarcoma, and macrophage (“Saibou Seicho Inshi Part II”, edited by the Japanese Tissue Culture Association, Asakura Shoten, 1987, p. 15-20). Basic fibroblast growth factor was initially named for its potent proliferative action on fibroblasts such as BALB/c3T3 cells (D. Gospodarowicz, Nature, vol. 249, p. 123 (1974)), but was later shown to promote the proliferation of most mesodermal cells, particularly of vascular endothelial cells (D. Gospodarowicz, National Cancer Institute Monograph, vol. 48, p. 109 (1978)), and to promote the proliferation of satellite cells of skeletal muscle (R. E. Allen, Experimental Cell Research, vol. 152, p. 154 (1984)). In recent years, there have been clinical applications of basic fibroblast growth factor in wound treatment, and applications of basic fibroblast growth factor for repairing blood vessel based on angiogenic action and the like.
Basic fibroblast growth factor has been reported to induce the proliferation of pulp cells and have a regulatory action on the differentiation of pulp cells into odontoblasts in vitro (M. Nakashima, Archs Oral Biol., vol. 37 (3), p. 231-236 (1992) and K. Nakao, Biochem Biophys Res Commun, vol. 325, p. 1052-1059 (2004)); it has been reported that TGF-β1 has a significant effect on the formation of repaired dentin, with no effect of basic fibroblast growth factor observed in vivo (D. Tziafas, Archs Oral Biol., vol. 43, p. 431-444 (1998) and C.-C. Hu, J. Endodontics, vol. 24(11), p. 744-751 (1998)).
For example, described as a basic fibroblast growth factor preparation in WO94/27630 is a crosslinked gelatin gel preparation containing basic fibroblast growth factor, useful for the treatment of bone disease; JP-A-7-233085 states that basic fibroblast growth factor and/or a homolog thereof possesses an excellent promoting effect on neogenesis or regeneration of cartilage tissue, and is useful for repair of cartilage tissue. JP-A-7-17876 discloses a therapeutic agent of periodontal disease comprising basic fibroblast growth factor and/or a homolog thereof. Furthermore, WO03/082321 discloses a viscous preparation for dental use comprising basic fibroblast growth factor, useful for the treatment of periodontal disease. The therapeutic agent of periodontal disease disclosed in JP-A-7-17876 is expected to find an application for the regeneration of dentin lost by dental caries (paragraph [0035] in the description of JP-A-7-17876). However, JP-A-7-17876 gives no disclosure or suggestion concerning the treatment of dental parenchyma loss due to dental caries caused by acid-producing bacteria such as Streptococcus mutans, tooth attrition or injury; there is a demand for the development of a therapeutic agent capable of radically treating dental parenchyma loss due to dental caries caused by acid-producing bacteria, tooth attrition or injury.